Abstract

Background: In this ongoing clinical exploratory study, FFPE tissue sections are probed for protein biomarkers along the PI3K/Akt/mTOR pathway. A panel of assays was developed using Layered Immunohistochemistry (L-IHC). L-IHC allows for concurrent measurement of 6-8 proteins (total and/or phosphorylation sites) using a single tissue section. The goal was to discover applications of the technique based on complementary rationales about the implications of pathway activation. Those were: 1) in a scenario where the test indicates drug target activation, analysis for a positive response to an mTOR-targeted tyrosine kinase inhibitor (everolimus and/or temsirolimus) in kidney cancer; or 2) analysis for predicting no response to a HER2-targeted drug (trastuzumab) in breast cancer, assuming a scenario where the test would indicate activation of a functional by-pass pathway.

Results: In the trastuzumab study, four biomarkers were determined to correlate with patient response. A total of 32 responders and 13 non-responders have been analyzed to date. The sum score for a 4-biomarker panel discriminated between responders and non-responders. The test correctly identified 28/32 responders and 10/13 non-responders for a sensitivity of 87%, specificity of 76%, and an accuracy of 81%.

In the mTOR inhibitor study, 35 RCC cases were analyzed, and a composite score based on 6 biomarkers was found to correlate to patient response. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%).

Conclusions: These results indicate that multiplexed protein analysis of tumor tissue is capable of providing scenario-specific information, which could help guide targeted therapy with either a positive or a negative clinical significance.

Funding source: Supported in part by NCI Grant 5R44CA123994-06 and by 20/20 GeneSystems.